We have previously demonstrated that therapy with cyclophosphamide (CP) was successful as a treatment for Wegener's granulomatosis (WG); however, drug toxicity has limited its use in many patients. Therefore, we evaluated the safety and efficacy of methotrexate (MTX) as an alternative therapy for WG. Results of these published studies demonstrated that MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. We have also investigated the potential for MTX to be used as maintenance therapy in patients in whom CP has induced a disease remission. In this protocol, patients receive prednisone plus CP therapy until remission of disease is achieved; CP is then switched to MTX for maintenance of remission. This CP/MTX regimen was highly effective and may represent a less toxic alternative to the standard CP regimen for patients with severe disease. We have also explored the use of other immunosuppressive drugs as remission maintenance agents. In a small open-label trial we investigated whether the immunosuppressive agent mycophenolate mofetil could be used in place of MTX for maintenance of CP-induced remission in patients with WG. Preliminary results of this study indicated that mycophenolate mofetil appeared to have efficacy in maintaining remission following CP therapy. In addition to these studies that utilize standard immunosuppressive drugs, we are also conducting 2 trials in patients with WG that utilized biologic agents that target specific cytokines involved in the inflammatory response. The first of these trials is designed to assess the safety, efficacy, and immunologic effects of a recombinant fusion protein that contains the extra cellular portion of the p75 TNF receptor linked to the Fc portion of human IgG1 (TNFR:Fc). We are seeking to examine whether TNFR:Fc is able to reduce the need for glucocorticoid treatment and lower relapse rates in patients with WG. The second trial investigates the safety and efficacy of daclizumab (a humanized monoclonal antibody that blocks the high-affinity interleukin-2 receptor on T cells) in the treatment of WG. This trial will seek to determine the efficacy of daclizumab in preventing disease relapses. In addition to our studies in WG we have recently initiated a phase I/I trial that will assess the safety and efficacy of Rituximab (a B cell depleting monoclonal antibody) in the treatment of patients with hepatitis C associated cryoglobulinemic vasculitis (HCV-CV).